A recent trend in the pharmaceutical industry has been the development of new drug delivery systems for both old and new drugs. Much of the current research in drug delivery technology is aimed at developing formulations and devices that improve the therapeutic effectiveness of drugs over conventional means of administration by controlling the rate, time and place of release of drugs in the body.
Conventional dosage types include sublingual (under the tongue), oral (capsules, tablets, liquids), injectable, nasal and parenteral (suppository and non-oral) forms. While oral dosage forms comprise a substantial majority of all present dosage forms and offer ease of administration and low cost-per-use, they can suffer from inconvenient dosing intervals, side effects and reduced efficacy. Conventional dosage forms have disadvantages in certain patients, including unpredictable blood levels, difficult or uncomfortable administration and poor compliance. In order to maintain optimum blood levels, some conventional forms of drug delivery require frequent doses which can be difficult to remember or understand, particularly for the elderly patient. Failure to comply with a recommended drug regimen can endanger a patient's health.
Controlled drug delivery systems have been introduced within the last decade to eliminate or reduce the limitations of conventional dosage forms. One type of controlled delivery is transdermal delivery, which involves delivery of a therapeutic agent through the skin for distribution within the body by the circulation of the blood. Transdermal delivery can be compared to continuous, controlled intravenous delivery of a drug using the skin as a port of entry instead of an intravenous needle. The therapeutic agent passes through the outer layers of the skin, diffuses into the capillaries, or tiny blood vessels in the skin, and then is transported into the main circulatory system.
Examples of drugs which have successfully been delivered transdermally include scopolamine for the treatment of motion sickness, nitroglycerin for the treatment of angina, estrogen and combined estrogen/progestogen for menopausal symptoms and osteoporosis, isosorbide dinitrate for angina, clonidine for hypertension, nicotine for smoking cessation, fentanyl for pain management and testosterone for male hypogonadism.
The hormone progesterone is used in the treatment of premenstrual syndrome, menopausal hormone replacement therapy (in combination with estrogen), infertility and a variety of gynecological conditions. The transdermal delivery of progesterone has been reported. However, due to the large size of the progesterone molecule, efforts to transdermally deliver progesterone in therapeutically effective amounts have often been unsuccessful. Progesterone is known to be metabolized within the skin by the 5-.alpha.-reductase enzyme which converts it to inactive 5-.alpha.-dihydroxyprogesterone (R. Sitruk-Ware, 1995, "Transdermal Application of Steroid Hormones for Contraception," J. Steroid Biochem. Molec. Biol. 53 (1-6):247-251). Thus, relatively high, multiple doses are required to elicit the desired progestational effect. The desired goal of transdermal delivery of progesterone is to be able to maintain consistent serum levels of progesterone at relatively low dosage levels without requiring multiple dosing.
Low rates of transdermal delivery of progesterone have been reported by various researchers. For example, Guy et al. (1987, "Kinetics of Drug Absorption Across Human Skin In Vivo," Pharmacol. Skin 1:70-76), disclose that about 1.2 .mu.g/cm.sup.2 penetrated in a 24-hour period, when the drug was applied as a thin film on the skin in vivo. Barry and Bennett, (1987, "Effect of Penetration Enhancers on the Permeation of Mannitol, Hydrocortisone, and Progesterone Through Human Skin," J. Pharm. Pharmacol. 39:535-546), report a rate of 0.477 .mu.g/cm.sup.2 /hour in vitro through excised human skin. Both Guy et al. and Barry and Bennett measured penetration through the skin after progesterone was applied in an acetone solution, the solvent was allowed to evaporate, and the skin surface was hydrated, either by occlusion or by application of a small amount of water. Barry and Bennett reported higher rates of transdermal penetration of progesterone when penetration enhancers were applied to the skin following application of the acetone/progesterone solution and evaporation of the solvent. Rates of 11.4 (+/-4.6) and 12.4 (+/-4.4) .mu.g/cm.sup.2 /hour, respectively, were observed after application of 2-pyrrolidone and N-methylformamide permeation enhancers. However, neither the methods nor the solvent vehicles for application of progesterone to the skin disclosed by these references are appropriate or practical for use in a transdermal patch delivery system, for number of reasons. Application of acetone to the skin commonly results in skin irritation, an effect that may also be encountered with 2-pyrrolidone and N-methylformamide. Further, permeation enhancers such as 2-pyrrolidone and N-methylformamide may impose health risks. Also, the volatile solvent carriers disclosed by these references can be difficult and impractical to incorporate into a patch system.
The transdermal delivery of progesterone, progestins, estrogens and testosterone from gel-like matrices has been reported. R. Sitruk-Ware (1988, "Innovative Technology for Hormonal Replacement Therapy," Maturitas, 10:79-81) discloses a progesterone cream for use as a topical therapy in benign breast diseases. R. Sitruk-Ware (1989, "Transdermal Delivery of Steroids," Contraception 39, (1):1-20) discloses that only small amounts of progesterone can be obtained in plasma via skin penetration, but when applied on the breast, high amounts of progesterone can be obtained in the breast tissue. A five-fold increase in progesterone concentration was demonstrated in breast tissue of women treated topically with the steroid dissolved in an alcohol/water gel.
Compounds that act as permeation enhancers have been added to transdermal drug delivery systems for a number of drugs, including progesterone. Pfister and Hsieh (1990, in "Permeation Enhancers with Transdermal Drug Delivery Systems: Part II: System Design Considerations," Pharmaceutical Technology, October 1990: 55-60), disclose a wide variety of permeation enhancers. For example, isopropyl palmitate and isopropyl myristate are disclosed as cosolvents to enhance the solubility of nitroglycerin in a polymer matrix-type transdermal system, which in turn optimizes the release of the drug from the system. Similarly, ethanol is disclosed as enhancing the solubility of 17-.beta.-estradiol in the reservoir compartment of a transdermal drug delivery device. Other skin penetration enhancers are disclosed, including stearyl alcohol, glycerol, 2-pyrrolidone, urea, propylene glycol, oleic acid, and palmitic acid. D. R. Friend (1990, "Transdermal Delivery of Contraceptives", Critical Reviews in Therapeutic Drug Carrier Systems 7 (2):149-186), discloses dimethyl sulfoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N,N-dimethyl-m-toluamide, urea, ethyl acetate, 1-dodecylazacycloheptan-2-one (azone), oleic acid and ethanol as permeation enhancers. Butylurea has also been disclosed as a permeation enhancer. For example, U.S. Pat. No. 5,128,376 discloses a method for percutaneous administration of a drug from a mixture of an adjuvant, a solvent and a diol/triol moderator, wherein the solvent, which enhances permeation, may be a substituted urea such as butylurea. U.S. Pat. No. 4,863,952 discloses an improved method of drug administration using a mixture comprising pyrrolidone carboxylic acid esters as percutaneous promoters, and optionally, substituted ureas such as butylurea. S. K. Han et al. (1991, "Percutaneous Absorption-Enhancing Activity of Urea Derivatives," Arch. Pharm. Res. 14(1):12-18) disclose the use of urea derivatives, including butylurea, to enhance the percutaneous absorption of salicylic acid and sodium salicylate from a vaseline base.
Hydrogels are well known in the art as vehicles for the controlled release of drugs. N. A. Peppas, ed., "Hydrogels in Medicine and Pharmacy," CRC Press, Inc. (1987) Vol. II, discloses the use of water soluble cellulose ethers such as methylcellulose for controlled release drug delivery systems. Volume III of the same publication discloses the release of progesterone from rod-shaped monolithic hydrogel devices.
U.S. Pat. Nos. 5,344,655 and 5,254,338 disclose that hydrogel bases containing water soluble polymers such as cellulose derivatives are known in the art for delivery of drugs through the skin. U.S. Pat. No. 4,693,887 discloses hydrogel compositions for the controlled release of contraceptives such as progesterone. The hydrogels are blends of either N-vinyl lactam or a copolymer of N-vinyl lactam and may further comprise spermicides such as urea. U.S. Pat. No. 5,405,366 discloses an adhesive hydrogel comprising an aqueous mixture of a radiation crosslinkable water-soluble polymer such as a polymer of N-vinyl-2-pyrrolidone and ethylene oxide and a humectant such as propylene glycol which may be used in a transdermal drug delivery system. The hydrogel may also contain preservatives such as propyl paraben and methyl paraben. U.S. Pat. No. 4,593,053 discloses a skin-compatible pressure-sensitive adhesive hydrogel comprising polyvinyl pyrrolidone and polyvinyl alcohol, a polar plasticizer or humectant such as propylene glycol, water and a drug. The composition may also contain cellulose derivatives to increase strength and guar gum to increase tackiness.
The transdermal delivery of progesterone, progestins, estrogens and testosterone from hydrogel matrices comprising permeation enhancers is also known. For example, U.S. Pat. No. 5,030,629 discloses transdermal formulations containing progesterone, ethanol, saline and an imidazoline penetration enhancer. Dosage forms of the formulations for application to the skin include gels, which may comprise inert carriers such as propylene glycol, urea and methylcellulose. U.S. Pat. No. 5,362,497 discloses compositions for transdermal delivery of, inter alia, androgens such as testosterone and estrogens such as estradiol comprising water- and fat-soluble absorption enhancers, and a water-absorbent resin such as a vinyl acetate-acrylic acid ester copolymer that swells to form a hydrogel upon contact with water. U.S. Pat. No. 5,064,654 discloses a transdermal drug formulation comprising a drug such as progesterone or estradiol, water and ethanol. The formulation may also contain an adhesive or gelling agent such as pectin, guar gum or methyl cellulose. U.S. Pat. No. 4,942,158 discloses a composition comprising a combination of isopropyl alcohol and isobutyl alcohol to enhance the transdermal penetration of steroids such as estradiol, or a combination of estradiol with a progestogen. The composition may also include water and a gelling agent such as methyl cellulose. U.S. Pat. No. 4,865,848 discloses compositions for enhancing the transdermal delivery of drugs, including progesterone, comprising sucrose esters as penetration enhancers. Preferably, the permeation enhancer and the drug are dispersed in a matrix which may be a gel or a hydrophilic polymer.
Despite their advantages, conventional transdermal delivery systems have been limited due to barrier properties of the stratum corneum, the skin's protective outer layer. Large, high molecular weight drugs such as progesterone are difficult to deliver through the skin in effective amounts. In general, the skin is highly resistant to permeation by chemicals, including drugs. Although the skin is only a few millimeters thick, the stratum corneum serves as a highly protective barrier against physical, chemical and bacterial penetration. This barrier primarily consists of dead skin cells bound together by certain fatty (lipid) materials. Generally, only drugs that are effective in the body at very low concentrations or that have particular physical properties have been successfully delivered through the skin in therapeutically effective amounts. High molecular weight drugs and drugs which are either charged or highly polar remain difficult to administer transdermally.
Natural progesterone, which is the form of progesterone that is produced by the body, has been administered in oral, injectable and suppository forms. The disadvantages of injectable and suppository forms are obvious: they are burdensome to administer. The disadvantage of oral forms is that they are short acting, and to maintain adequate blood levels, they have to be dosed throughout the day. The bulk of orally administered progesterone is metabolized by the digestive system and excreted before it can be used by the body. In fact, progesterone, whether administered orally, vaginally or rectally, has a half life in the body of only about 2.2 hours. Therefore, much larger amounts than the body actually requires must be dosed to maintain effective blood levels.
To address the problems associated with conventional means of administration of natural progesterone, a variety of synthetic forms, known as progestins, have been developed. Progestins fall primarily into two categories. The first group, pregnanes, is derived from 17-.alpha.-acetoxy progesterone. A classic example is medroxy progesterone acetate (Provera). With an increased affinity for progesterone receptors, these compounds have marked progestational activity. They possess anti-estrogenic anti-gonadotropic, and no significant androgenic properties. A second group, estranes, derived from 17-.alpha.-ethinyl-1-nortestosterone, includes norethindrone acetate (aygestin). Besides progestational activity, these compounds have marked anti-estrogenic, some anabolic, moderate androgenic, and as a result, pronounced anti-gonadotropic activities.
Synthetic progesterones are 10-100 times more potent than natural progesterone, and thus are effective at much lower doses. However, synthetic progesterones (i.e., progestins) can cause many negative side effects, such as sudden or partial loss of vision, thrombophlebitis, pulmonary embolism, cerebral thrombosis, salt and fluid retention, epilepsy, migraine, asthma, cardiac or renal dysfunction, weight gain, rise in blood pressure, headaches, depression, decreased glucose tolerance leading to diabetes in predisposed individuals, acne, alopecia, hirsutism, decrease in T3 uptake and thyroid regulation.
A disadvantage of conventional patch systems is that many of them either incorporate drugs in an adhesive or require an adhesive to affix the patch to patient's skin. These adhesives can irritate the skin, causing patient non-compliance. Thus, there is a need for a non-adhesive transdermal delivery system that can deliver therapeutically effective amounts of hormones such as natural progesterone, progestins, estrogens and testosterone that will reduce or eliminate the skin irritation experienced by many patients using current adhesive patch transdermal delivery systems. This need is satisfied by a particular embodiment of the invention.
Although patches for the transdermal delivery of estrogen and testosterone are currently commercially available, progesterone can be obtained commercially at present only in oral, injectable and suppository forms. The transdermal delivery of natural progesterone from hydrogel matrix systems with potential for use in patches has been demonstrated; however, none of these systems has proven adequate for administration of therapeutically effective amounts of progesterone. Accordingly, there is a need in the art for a matrix composition that can transdermally deliver and maintain therapeutically effective levels of hormones such as natural progesterone, progestins, estrogens and testosterone in the bloodstream from a convenient, reliable patch system.
Citation of the references hereinabove shall not be construed as an admission that such references are prior art to the present invention.